Bone functions as a supporting organ for the body and as a well organized dynamic system consisting of mineral, a matrix of collagen fibers, and cells. The cells include osteocytes, osteoblasts, and osteoclasts. The cells comprise 3-4% of the total volume. The collagen fibers are spatially oriented, highly organized into interlacing bundles and layers, and embedded in a gelatinous mucopolysaccharide ground substance which makes up 4-5% of the organic bone matrix. The mucopolysaccharides are covalently linked to noncollagenous proteins in combination with collagen to form a matrix of connective tissue. This protein matrix makes up 35% of the intercellular bone material, with minerals, mainly calcium, occupying the remainder.
Bone maturation is dependent upon activity of osteoblasts as well as certain bioelectrical fields in bone which are constantly produced by mechanical stress. The bioelectrical fields influence the spatial orientation of collagen fibrils and direct the structural development of the new bone as the bone material is mineralized.
Bone resorption is characterized by concomitant dissolution of both the bone matrix and mineral, and associated with osteoclasts and osteocytes. The method by which bone is dissolved is largely unknown. Collagenase, lysosomal proteases, and H+ are involved in solubilization of the mineral. The H+ is produced from organic acids and carbonic anhydrase derived from osteoclasts. Osteocytes are also involved in cortical bone resorption, releasing alkaline phosphatase, proteases, and lysosomal acid hydrolases. A variety of hormones and metabolic agents further control the balance between calcium and other minerals in bone and the circulating mineral pool.
Bone tissue is constantly undergoing remodeling and turnover via the slow process of bone formation and resorption. The amount of remodeling and turnover is age-dependent with rapid, 100% turnover in infants to slower 18% turnover in adults per year. Bone lability is maintained by concurrent, balanced activities of bone formation and resorption. Imbalances in the bone formation/resorption process lead to a variety of bone diseases.
Arthritis is a musculoskeletal disorder involving inflammation of the joints and its effects. Joint disease is one of the leading causes of activity limitations in the elderly. In its acute form, arthritis is marked by pain, inflammation, redness and swelling. There are three principle forms of arthritis: osteoarthritis, rheumatoid arthritis, and septic arthritis.
Osteoarthritis, also called osteoarthrosis or degenerative joint disease, is a disorder of the joints characterized by progressive deterioration of the articular cartilage. When the articular cartilage deteriorates by abrasion or wear, the bones change or shrink affecting the articular or hinge surfaces, causing further joint damage and pain. While the disease may be asymptomatic at early times, it later progresses to pain, stiffness, and limitation in movement. Common sites of discomfort are hips, knees, and vertebrae, i.e., joints that bear much of the weight of the body. The clinical manifestations of osteoarthritis and its subsequent treatment vary with the location and severity of the joint damage. Moderate symptoms are generally treated with combinations of any or all of analgesic and anti-inflammatory drugs, periodic rest, weight reduction, injection of corticosteroids, and physical therapy or exercise. More serious symptoms may be treated with invasive surgical procedures such as hip or knee replacement or joint debridement, i.e., removal of damaged tissue.
Rheumatoid arthritis is a chronic, progressive disorder in which the soft tissues of the joint become inflamed, irreversibly damaging joint cartilage and replacing it with deforming deposits of scar tissue. Rheumatoid usually affects joints of the body symmetrically such as both hands, feet, knees, hips, shoulders, and wrists. Serious incapacitation results in an estimated one-third of all cases. Rheumatoid arthritis is characterized by a gradual onset, beginning with pain and stiffness in one or more joints, usually followed by swelling and heat, muscle dysfunction and pain. Fatigue, muscle weakness, weight loss, and the presence of a characteristic autoantibody, i.e, rheumatoid factor, are also commonly present. Treatment for pain and disability include analgesics such as aspirin and ibuprofen which have anti-inflammatory properties. Small doses of corticosteroids such as prednisone may be prescribed when large doses of analgesics do not relieve pain and inflammation. Physical therapy is useful in relieving pain and swelling in the affected joints. Rest is also suggested during acute stages to prevent deformity. In severe cases, surgery may be used to replace destroyed hip, knee or finger joints.
Septic arthritis results from an infection in connective tissues generally caused by some form of invasive trauma. Pain and inflammation are associated with the infected tissue. Treatment generally involves use of antibiotic and/or antifungal agents as well as analgesic, anti-inflammatory, and antipyretic drugs for pain and inflammation.
The analgesic and anti-inflammatory drugs of choice for all three forms of arthritis are nonsteroidal anti-inflammatory drugs (NSAIDS) which provide relief from the pain and inflammation associated with arthritis. These drugs include salicylic acid derivatives such as aspirin; indole and indene acetic acids such as indomethacin, sulindac, and etodolac; heteroaryl acetic acids such as diclofenac; arylpropionic acids such as ibuprofen and naproxen; fenamates; and alkanones such as apazone. While these drugs show varying strengths in analgesic, anti-inflammatory, and antipyretic properties, they also have unwanted side effects. The most common is gastrointestinal side effects including gastric and/or intestinal ulceration, dyspepsia, and heartburn. Other side effects include disturbances in platelet function, the prolongation of gestation or spontaneous labor, and changes in renal function.
While providing relief from the symptoms of arthritis, these drugs do not arrest the progression of the course of the arthritic disorder. There is a need for drugs which will decrease joint damage as well as provide relief from the pain and inflammation associated with the disease process.
For rheumatoid arthritis, studies indicate that proinflammatory cytokines, particularly tumor necrosis factor (TNF), play a significant role in its pathogenesis, acting as an immune modulator in acute and chronic inflammation (Moreland, et al., "Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein," New England J Med 337:141-147 (1997); Arend, W. P. and Dayer, J. M., "Inhibition of the production and effects of interleukin-1 and tumor necrosis factor .alpha. in rheumatoid arthritis," Arthritis Rheum 38:151-160 (1995); Brennan, F. M. and Feldmann, M., "Cytokines in autoimmunity," Curr Opin Immunol 4:754-759 (1992)). Persons with active rheumatoid arthritis have an increased TNF concentration in the synovial fluid, and increased TNF plasma levels are associated with joint pain in rheumatoid arthritis patients. Administration of TNF antagonists to patients with rheumatoid arthritis has been shown to reduce symptoms (Elliott, et al., "Repeated therapy with monoclonal antibody to tumor necrosis factor .alpha. (cA2) in patients with rheumatoid arthritis," Lancet 344:1125-1127 (1994); Elliott, et al., "Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor .alpha. (cA2) versus placebo in rheumatoid arthritis," Lancet 344:1105-1110 (1994); Elliott, et al., "Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor .alpha.," Arthritis Rheum 36:1681-1690 (1993); Rankin, et al., "The therapeutic effects of an engineered human anti-tumor necrosis factor alpha antibody (CDP571) in rheumatoid arthritis," Br J Rheumatol 34:334-342 (1995)). Therefore, it is desirable to identify new substances which are capable of acting as antagonists of proinflammatory cytokines such as TNF. Particularly, it is desirable to identify new substances capable of diminishing the deleterious effects of TNF-.alpha. in rheumatoid arthritis patients.
The normal supportive function of bone requires an adequate supply of amino acids for the synthesis of collagen as well as calcium and phosphate for mineralization. The growth, repair and remodeling of bone tissue also require a precisely regulated supply of hormones, vitamins, and enzymes. Skeletal disease or abnormality caused by inadequacies in the supply or action of these essential elements is termed metabolic bone disease. Osteoporosis is one example of metabolic bone disease.
Osteoporosis is a condition of low bone tissue mass per unit volume and skeletal weakness that results in fractures with minimal trauma. Characteristic sites of fracture include the neck, humerus, tibia, wrist, and pelvis. Bone resorption is increased, and while bone formation appears to be normal, there may be a decrease in the quality of bone tissue formed. Osteoporosis is generally described as primary or secondary. Secondary osteoporosis may result from systemic illness (e.g., diabetes mellitus, hyperthyroidism, hypogonadism, chronic renal failure, rheumatoid arthritis, and malignancy) or medications (e.g., corticosteroids, ethanol, tobacco, barbiturates, and heparin). Treatment of secondary osteoporosis generally involves resolution or management of the underlying cause.
There are three types of primary osteoporosis: idiopathic, Type I, and Type II. Idiopathic osteoporosis occurs in children or young adults of both sexes with normal gonadal function. Type I osteoporosis (postmenopausal osteoporosis) is loss of trabecular bone due to estrogen lack at menopause. It occurs between the ages of 51 and 75 years and is more prevalent in women than in men. Vertebral crush fractures are common in Type I osteoporosis. It is generally caused by postmenopausal endocrinologic changes. Type II osteoporosis is loss of cortical and trabecular bone due to long-term remodeling inefficiency, dietary inadequacy, and activation of the parathyroid axis with age. It occurs in those of greater than 70 years, is twice as common in women than in men, and is more gradual and age-related. Type II osteoporosis may be associated with age-related reduction in vitamin D synthesis or resistance to vitamin D activity. In women, Type I and Type II osteoporosis may exist together.
The primary regulators of adult bone mass include physical activity, reproductive endocrine status, and calcium intake. Optimal maintenance of bone requires sufficiency in all three areas, and deficiency in one area cannot be compensated by excessive attention in the other areas. Prevention for osteoporosis calls for regular physical activity, attention to nutritional status in children and elderly with increased dietary calcium and/or vitamin D, and estrogen replacement in menopausal women. Current symptomatic treatment for osteoporosis involves orthopedic support devices, analgesics, heat, massage, and hyperextension exercises.
Pharmacological treatment for osteoporosis involves administration of agents which either decrease the rate of bone resorption and thus slow the rate of bone loss or increase the rate of bone formation. The only drugs approved for use in the United States are those that decrease bone resorption. Antiresorptive drugs include supplemental calcium, vitamin D and its analogs, menopausal estrogen replacement, calcitonin (inhibitor of osteoclastic bone resorption), bisphosphonates (inhibitor of osteoclastic bone resorption), and thiazide diuretics (inhibit urinary Ca++ excretion and constrain bone loss). Bone-forming agents include fluoride, androgens, and parathyroid hormone.
Antiresorptive treatment successfully maintains but does not increase bone mass. Agents that stimulate new bone formation are either problematic or experimental. Consequently, strategies for increasing bone mass in osteoporosis patients remains elusive. Combination therapies involving antiresorptive and bone-forming agents have been used with some success to offset negative side effects of any one agent, but the long-term effects of such treatment is unknown. Therefore, new methods by which bone resorption is decreased and/or bone mass is increased with minimal side effects are desirable.